Lamotrigine oral liquid suspension and use thereof

ABSTRACT

The present invention relates to an oral liquid suspension that includes lamotrigine and methods of medical treatment that include administering the oral liquid suspension. The oral liquid suspension has desirable physicochemical properties and technical attributes. The oral liquid suspension is useful in patients having difficulties in swallowing tablets and provide medical practitioners with additional options for dose titration.

RELATED U.S. APPLICATION DATA

This application claims priority to provisional patent applicationnumber 62/853,800 filed on May 29, 2019; the contents of which areincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsyand bipolar disorder. For epilepsy it is used to treat partial seizures,primary and secondary tonic-clonic seizures, and seizures associatedwith Lennox-Gastaut syndrome. Lamotrigine also acts as a moodstabilizer. It is the first medication since lithium to be grantedapproval by the U.S. Food and Drug Administration (FDA) for themaintenance treatment of bipolar type I. Chemically unrelated to otheranti convulsants (due to lamotrigine being a phenyltriazine),lamotrigine has relatively few side-effects and does not require bloodmonitoring in monotherapy. The exact way lamotrigine works is currentlyunknown. Some think that it is a Na⁺ (sodium) channel blocker, though itis interesting to note that lamotrigine shares very few side-effectswith other, unrelated anticonvulsants known to inhibit sodium channels,(e.g. oxcarbazepine), which may suggest that lamotrigine has a differentmechanism of action.

Lamictal® (lamotrigine) is available as scored tablets (25 mg, 100 mg,150 mg and 200 mg) and chewable dispersible tablets (2 mg, 5 mg and 25mg). Five-week sample kits are also available; these include titrationinstructions and scored tablets (25 mg for patients taking valproate, 25mg and 100 mg for patients not taking valproate). Lamotrigine is alsoavailable in un-scored tablet form. In 2005, Teva PharmaceuticalIndustries Ltd. began selling generic lamotrigine in the United States,but only in 5 mg and 25 mg chewable dispersible tablets. On 23 Jul. 2008Teva began offering the full line of generic lamotrigine in the US.Lamotrigine is also available in generic form in the United States, theUnited Kingdom and Canada.

Lamotrigine is BCS class II molecule with low solubility and highpermeability. Oral administration is associated with a delayed onset ofthe desired pharmacological action as lamotrigine is a poorly soluble inwater which causes low rate of dissolution of the drug in aqueous mediaincluding biological fluids like gastrointestinal fluid. It is alsodifficult to formulate lamotrigine into a suspension dosage form due tovarious challenges like bitter taste of the drug and maintaining thechemical stability of the drug in the suspension dosage form. Further,the formulated suspension should exhibit desirable technical attributeslike pourability, viscosity, dissolution, stability, re-suspendabilityand re-dispersibility complying with demanding requirements andregulations of health and medicine regulatory agencies across the world,especially USFDA, EMEA, Health Canada, MHRA and TGA.

Currently, there are no liquid formulations of lamotrigine commerciallyavailable and, as a result, hospital pharmacists are often required tocompound liquid formulations using crushed lamotrigine tablets forpediatric patients and patients who cannot swallow tablets. A needtherefore exists for an improved formulation of lamotrigine.

Several oral dosage forms containing lamotrigine are believed to existand offered for sale outside the U.S. It is believed that no oral liquidsuspension containing lamotrigine has yet received approval from theU.S. Food and Drug Administration (FDA). As such, it is currentlyunknown whether an oral liquid suspension containing lamotrigine hasbeen successfully developed, while achieving the desired strength oflamotrigine and performance characteristics, as required for FDAapproval. These performance characteristics include, e.g.,pharmacokinetic (PK) profile (e.g., AUC, C_(max), t_(max), and t_(1/2)),stability, redispersibility, and dissolution. It is therefore alsounknown whether any such oral liquid suspension would further possessthe desired physical dimensions, physical properties, and/or performancecharacteristics (e.g., pH, viscosity, specific gravity, and/or suitabletaste) to be manufactured on a commercial scale, while demonstrating tothe FDA that the oral liquid suspension is safe and effective toconsumers for its intended use. This also includes formulating andconfiguring the oral liquid suspension to deliver the lamotrigineenterally, given the administration is oral.

SUMMARY OF THE INVENTION

The present invention provides for an oral liquid suspension thatincludes: lamotrigine, preservative, sweetener, solvent, anticakingagent, viscosifying agent, suspending agent, pH adjuster, andtaste-masking agent.

The present invention also provides for an oral liquid suspension thatincludes: lamotrigine, preservative, sweetener, solvent, anticakingagent, viscosifying agent, suspending agent, flavoring agent, colorant,pH adjuster, and taste-masking agent.

The present invention also provides for an oral liquid suspension thatincludes: 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine (lamotrigine);water; glycerin; propylene glycol; polyethylene glycol 400;methylparaben; sodium benzoate; sorbitol; saccharin sodium; sucralose;xanthan gum; sodium carboxymethyl cellulose; sodium phosphate dibasic;PROSOLV® SMCC 50 M (microcrystalline cellulose and colloidal silicondioxide); optionally a coloring agent; and optionally a flavoring agent.

The present invention also provides for an oral liquid suspension thatincludes: 1±0.1% (w/v) 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine(lamotrigine); 84.75±8.5% (w/v) water; 3.25±0.33% (w/v) glycerin (99%natural); 2.25±0.23% (w/v) propylene glycol; 3.00±0.3% (w/v)polyethylene glycol 400; 0.1±0.01% (w/v) methylparaben; 0.03±0.003%(w/v) sodium benzoate powder; 2.1±0.21% (w/v) sorbitol (3% of 70%solution); 0.08±0.008% (w/v) saccharin sodium dihydrate powder;0.75±0.08% (w/v) sucralose; 0.20±0.02% xanthan gum; 0.10±0.01% (w/v)sodium carboxymethyl cellulose (medium viscosity 2% aqueous solution at25C 400-800 cPs); 0.03±0.01% (w/v) sodium phosphate dibasic (dried);1.26±0.15% (w/v) PROSOLV® SMCC 50 M (microcrystalline cellulose andcolloidal silicon dioxide); 0.2±0.05% (w/v) cherry flavor (natural andartificial); 0.002±0.0002% (w/v) FD&C red #40; and 0.0002±0.00002% (w/v)FD&C yellow #6.

The composition described herein is an oral liquid suspension and not,e.g., an oral solution. As such, the active ingredient, lamotrigine, isnot fully dissolved but is essentially suspended therein. While theactive ingredient may be only slightly dissolved therein, the lack of itbeing fully dissolved could otherwise pose stability issues. As an oralliquid suspension, the active ingredient will typically settle to thebottom of the container during extended periods of time during theshipmen and storage. Effectively resuspending the active ingredient willneed to be carried out prior to use. Additionally, the active ingredient(lamotrigine) is unpleasant tasting.

The composition described herein is an oral liquid suspension thatincludes a suspending agent, viscosifying agent, anticaking agent, andredispersing agent. Achieving a suitable stability of the suspendedactive ingredient is achieved in part by modifying the pH of thecomposition. Achieving a suitable stability of the suspended activeingredient is also achieved in part by controlling the particle sizedistribution as well as the water content of the active ingredient.Including a suitable flavoring agent provides a composition that isrelatively pleasant tasting. The oral liquid suspension, compared to thesolid oral dosage form (e.g., tablets) containing lamotrigine, istherefore (i) convenient to use, (ii) has a relatively quick onset ofaction, (iii) can be used with children and the elderly who often havedifficulties swallowing, and (iv) the dose can readily be titrated.Additionally, the above is achieved while providing for an oral liquidsuspension (v) having a suitable redispersibility, (vi) is relativelystable, (vii) is relatively pleasant tasting, (viii) upon shaking willbe substantially devoid of lumps or clumps, even after long storage,(ix) possesses good pourability, (x) has good physical stabilityproperties such as low level of sedimentation (reduced or no caking),(xi) has easy redispersion on agitation, and (xii) provides for doseuniformity during each administration.

The present invention also provides for a method for treating at leastone of a neurological disorder and a mental disorder in a subject. Themethod includes administering to a subject suffering from the disorderan oral liquid suspension described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more readily understood by reading thefollowing detailed description of the invention and study of theincluded examples.

The present invention is based, in part, upon the discovery of noveloral liquid suspensions that provide advantages when used for the invivo delivery to a mammal of the active pharmaceutical ingredient (API)lamotrigine. In doing so, the present invention provides for oral liquidsuspensions that provide for a suitable therapeutic index and/or lowerincidence, severity, or duration of adverse reaction(s) compared topreviously described dosage forms containing the active ingredient inthe same amount.

The oral liquid suspensions may be used for a variety of purposes,including for the in vivo delivery of the active pharmaceuticalingredient (API) lamotrigine. Accordingly, the present invention furtherprovides methods of treating diseases or disorders (e.g., neurologicaldisorder and/or a mental disorder), such as epilepsy and/or bipolardisorder.

Relative to oral tablets or chewable dispersible tablets containing anequivalent amount of lamotrigine, administration of the oral liquidsuspension may result in a lower incidence, severity, and/or duration ofadverse reactions including at least one of dizziness, headache,diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis,pharyngitis, rash, vomiting, infection, fever, accidental injury,diarrhea, abdominal pain, tremor, backpain, fatigue, and xerostomia.

In forming an oral liquid suspension, any one or more of the excipientsemployed can effectively be dissolved or dispersed therein (e.g., in thesolvent). This includes, e.g., salts, such as sodium benzoate, saccharinsodium, and sodium carboxymethyl cellulose. In doing so, the salt candissociate into the respective anion and cation, and would therefore nolonger necessarily exist in the salt form—benzoic acid, saccharin, andcarboxymethyl cellulose. However, within the context of the invention,it is appreciated that those of skill in the art understand and agreethat reference to the oral liquid suspension as containing the salt formis otherwise acceptable and appropriate.

Likewise, in specific embodiments, lamotrigine (having a specifiedparticle size distribution (PSD)) can be employed in the manufacture ofthe oral liquid suspension. In forming the oral liquid suspension, thelamotrigine present therein can effectively be suspended and/ordissolved therein (e.g., in the solvent). In doing so, the lamotriginewould therefore no longer necessarily retain the PSD. However, withinthe context of the invention, it is appreciated that those of skill inthe art understand and agree that reference to the oral liquidsuspension as containing the lamotrigine as having a specified PSD(based on the lamotrigine employed) is otherwise acceptable andappropriate. Alternatively, reference to the oral liquid suspension ascontaining the lamotrigine as having a specified PSD (based on thelamotrigine present in the oral liquid suspension) is also acceptableand appropriate. As such, the PSD of the lamotrigine employed is often aparameter for the PSD of lamotrigine present in the oral liquidsuspension.

The articles “a” and “an” as used herein refers to “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement or component of an embodiment by the indefinite article “a” or“an” does not exclude the possibility that more than one element orcomponent is present.

The term “excipient” refers to a pharmacologically inactive componentpresent in the oral liquid suspension. Excipients include, e.g.,preservatives, sweetening agents, solvents, anticaking agents,viscosity-increasing agents, suspending agents, acidifying agents,flavoring agents, and colorants. The excipients used in preparing theoral liquid suspension described herein are safe and non-toxic. Suitableexcipients are disclosed in Handbook of Pharmaceutical Excipients, Roweet al., Eds., 8th Edition, Pharmaceutical Press (2017).

The term “preservative” refers to a substance that is added to products,such as oral liquid suspensions, to prevent decomposition by microbialgrowth or by undesirable chemical changes. In general, preservation isimplemented in two modes, chemical and physical. Suitable preservativesinclude, e.g., one or more of ethanol, benzoic acid, benzyl alcohol,bronopol, butylated hydroxyanisole (BHA), butylparaben, calcium acetate,calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride,chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acidmonohydrate, ethylparaben, glycerin, hexetidine, imidurea, isopropylalcohol, lactic acid, methylparaben, monothioglycerol, parabens,pentetic acid, phenoxyethanol, phenylethyl alcohol, potassium benzoate,potassium metabisulfite, potassium sorbate, propionic acid, propylgallate_(;) propylene glycol, propylparaben, propylparaben sodium,sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodiummetabisulfite, sodium propionate, sodium sulfite, sorbic acid,sulfobutyl ether β-cyclodextrin, edetic acid, thimerosal, and xanthan.

The term “sweetening agent” or “sweetener” refers to a substance that isadded to products, such as oral liquid suspensions, to provide a sweettaste like that of sugar. The sweetener can include, e.g., one or moreof acesulfame potassium, alitame, aspartame, dextrose, erythritol,fructose, glycerin, isomalt, lactitol, glucose, maltitol, maltose,mannitol, monk fruit extract, neohesperidin dihydrochalcone, neotame,saccharin, saccharin sodium, sodium cyclamate, sorbitol, stevia,sucralose, sucrose, tagatose, thaumatin, trehalose, and xylitol.

The term “solvent” refers to a substance that is added to products, suchas oral liquid suspensions, to dissolve the active pharmaceuticalingredient (API) and/or excipients. The solvent can include, e.g., oneor more of albumin, ethanol, almond oil, benzyl alcohol, benzylbenzoate, butylene glycol, castor oil, corn oil (maize), cottonseed oil,dimethyl ether, dimethylacetamide, ethyl lactate, ethyl oleate,glycerin, isopropyl alcohol, isopropyl myristate, isopropyl palmitate,light mineral oil, medium-chain triglycerides, methyl lactate, mineraloil, monoethanolamine, octyldodecanol, olive oil, peanut oil,polyethylene glycol, polyoxyl castor oil, propylene carbonate, propyleneglycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunfloweroil, triacetin, tricaprylin, triethanolamine, triethyl citrate,triolein, and water.

The term “anticaking agent” refers to a substance that is added toproducts, such as oral liquid suspensions, to prevent or decrease theoccurrence of agglomeration of particles, such as the activepharmaceutical ingredient (API) and/or excipients. The anticaking agentis added to prevent or decrease the formation of lumps (caking), whichprovides for ease in packaging, transport, flowability, and consumption.The anticaking agent can include, e.g., one or more of tribasic calciumphosphate, calcium silicate, colloidal silicon dioxide, hydrophobiccolloidal silica, magnesium oxide, magnesium silicate, magnesiumtrisilicate, and talc.

The term “viscosity-increasing agent” refers to a substance that isadded to products, such as oral liquid suspensions, to increase theviscosity. The viscosity increasing agent is used in order to impart anappropriate viscosity to the oral liquid suspension. The viscosityincreasing agent increases the viscosity of the oral liquid suspensionwithout substantially changing its other properties. Theviscosity-increasing agent can include, e.g., one or more of acacia,agar, alginic acid, bentonite, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, ceratonia, cetostearylalcohol, chitosan, colloidal silicon dioxide, cyclomethicone,ethylcellulose, gelatin, glycerin, guar gum, hectorite, hydrogenatedvegetable oil type I, hydrophobic colloidal silica, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,hydroxypropyl starch, hypromellose, magnesium aluminum silicate,maltodextrin, methylcellulose, myristyl alcohol, polydextrose,polyethylene glycol, polyvinyl alcohol, potassium chloride, povidone,propylene glycol alginate, saponite, sodium alginate, sodium chloride,starch, stearyl alcohol, sucrose, sulfobutyl ether β-cyclodextrin,tragacanth, and xanthan gum.

The term “suspending agent” refers to a substance that helps the activepharmaceutical ingredient (API) stay suspended in the oral liquidsuspension and prevents caking at the bottom of the container. One ofthe properties of a well-formulated oral liquid suspension is that itcan be easily re-suspended by the use of moderate agitation or shaking.The suspending agent can include, e.g., one or more of acacia, agar,alginic acid, bentonite, calcium stearate, carbomers,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carrageenan, powdered cellulose, cellulose, microcrystalline cellulose,carboxymethylcellulose sodium, ceratonia, colloidal silicon dioxide,dextrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, hypromellose, kaolin, magnesium aluminum silicate, maltitolsolution, medium-chain triglycerides, methylcellulose, silicifiedmicrocrystalline cellulose, phospholipids, polycarbophil, polyethyleneglycol, polyoxyethylene sorbitan fatty acid esters, potassium alginate,povidone, propylene glycol alginate, saponite, sesame oil, sodiumalginate, sodium starch glycolate, sorbitan esters, sucrose, tragacanth,vitamin E polyethylene glycol succinate, and xanthan gum. Additionally,the suspending agent can include, e.g., PROSOLV® SMCC 50M(microcrystalline cellulose and colloidal silicon dioxide).

The suspending agent is able to reduce the formation of lamotriginehydrate. Exemplary hydrate forms of lamotrigine hydrate are described inU.S. Pat. Nos. 8,486, 927 and 7,390,807. In some embodiments, less thanabout 8 wt. %, less than about 5 wt. %, less than about 3 wt. %, lessthan about 1 wt. %, or less than about 0.5 wt. % of the lamotriginethereof is converted into its hydrate form over the period of time ofmanufacturing, shipping, and storage of the oral liquid suspensiondescribed herein (e.g., up to 6-9 months) under ambient conditions.

The suspending agent also contributes to the stability of the suspensionafter reconstitution. In some embodiments, less than about 5 wt. %, lessthan about 3 wt. %, less than about 1 wt. %, less than about 0.5 wt. %,less than about 0.2 wt. %, or less than about 0.1 wt. % of thelamotrigine is decomposed over the period of time of manufacturing,shipping, and storage of the oral liquid suspension described herein(e.g., up to 6-9 months) under ambient conditions.

The term “acidifying agent” refers to a substance that is added toproducts, such as oral liquid suspensions, to lower the pH, or is addedto achieve a desired pH that is lower than it would otherwise be in theabsence of the acidifying agent. The acidifying agent can include, e.g.,one or more of sodium phosphate dibasic, adipic acid, ammonium chloride,citric acid monohydrate, diluted hydrochloric acid, lactic acid,propionic acid, and tartaric acid.

The term “flavoring agent” refers to a substance that gives anothersubstance flavor, altering the characteristics of the solute, causing itto become sweet, sour, tangy, etc. A flavor is a quality of somethingthat affects the sense of taste. The flavoring agent can include, e.g.,cherry flavor, grape, or peppermint.

The term “colorant” or “coloring agent” refers to substance that isadded or applied in order to change the color of a material or surface.Colorants work by absorbing varying amounts of light at differentwavelengths (or frequencies) of its spectrum, transmitting (iftranslucent) or reflecting the remaining light in straight lines orscattered. The colorant can include, e.g., FD&C red #40, FD&C yellow #6,or a combination thereof.

The term “oral liquid suspension” refers to a pharmaceutical dosage formthat is a liquid and is orally administered. It includes lamotriginemixed with a liquid vehicle for oral administration. Being a suspension,the dosage form consists of undissolved particles (e.g., lamotrigineand/or excipients). The undissolved particles can be suspended in theoral liquid suspension. Alternatively, the undissolved particles cansettle to the bottom of the container where it can be shaken and/oragitated to resuspend in the solution.

The term “lamotrigine” refers to the compound chemically designated as6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, having the chemicalformula C₉H₇Cl₂N₅ and molar mass of 256.091 g/mol. In specificembodiments, the lamotrigine functions as the sole active ingredient.The lamotrigine used herein will also have a suitable particle sizedistribution (PSD). Lamotrigine, unless otherwise specified, includesthe free base, pharmaceutically acceptable salts thereof, isomers, andpolymorphs thereof. Lamotrigine is commercially available in multiplephysical forms (e.g., amorphous or crystalline forms). A micronizedamorphous form is commercially available from Torrent Pharmaceuticals(Ahmedabad, India).

The term “glycerin” or “glycerol” refers to the compound chemicallydesignated as propane61,2,3-triol, having the chemical formula C₃H₈O₃and molar mass 92.094 g/mol. The glycerin can be glycerin, 99% natural.When present in the oral liquid suspension described herein, theglycerin can function as a preservative, sweetening agent, solvent,viscosity-increasing agent, or any combination thereof.

The term “propylene glycol” refers to the compound chemically designatedas propane-1,2-diol, having the chemical formula C₃H₈O₂, and molar mass76.095 g/mol. When present in the oral liquid suspension describedherein, the propylene glycol can function as a preservative, solvent,viscosity-increasing agent, or any combination thereof.

The term “polyethylene glycol” or “PEG” refers to the compoundchemically designated as poly(oxyethylene) or PEO (also referred to aspoly(ethylene oxide) or PEO), having the chemical formulaC_(2n)H_(4n+2)O_(n+1), and molar mass 18.02+44.05 n g/mol. PEG, PEO, andPOE refer to an oligomer or polymer of ethylene oxide. The three namesare chemically synonymous, but historically PEG is preferred in thebiomedical field, whereas PEO is more prevalent in the field of polymerchemistry. Because different applications require different polymerchain lengths, PEG has tended to refer to oligomers and polymers with amolecular mass below 20,000 g/mol, PEO to polymers with a molecular massabove 20,000 g/mol, and POE to a polymer of any molecular mass. Pais aretypically prepared by polymerization of ethylene oxide and arecommercially available over a wide range of molecular weights from 300g/mol to 10,000,000 g/mol. When present in the oral liquid suspensiondescribed herein, the polyethylene glycol can function as a solvent,viscosity-increasing agent, suspending agent, or any combinationthereof.

The polyethylene glycol can be polyethylene glycol 400. The term“polyethylene glycol 400” refers to a low-molecular-weight grade ofpolyethylene glycol, having the chemical formula C_(2n)H_(4n+2)O_(n+1),wherein n=8.2 to 9.1, and molar mass 380-420 g/mol. When present in theoral liquid suspension described herein, the polyethylene glycol 400 canfunction as a solvent, viscosity-increasing agent, suspending agent, orany combination thereof.

The term “methylparaben” refers to the compound chemically designated asmethyl 4-hydroxybenzoate, having the chemical formula C₈H₈O₃, and molarmas 152.149 g/mol. When present in the oral liquid suspension describedherein, the methylparaben can function as a preservative.

The term “sodium benzoate” refers to the compound benzoate of soda,having the chemical formula C₇H₅NaO₂, and molar mass 144.105 g/mol. Whenpresent in the oral liquid suspension described herein, the sodiumbenzoate can function as a preservative.

The terra “sorbitol” refers to the compound chemically designated as(2S,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol, having the chemical formulaC₆H₁₄O₆, and molar mass 182.17 g/mol. The sorbitol can be solidsorbitol. Alternatively, the sorbitol can be in solution (e.g., 70%solution of sorbitol). When present in the oral liquid suspensiondescribed herein, the sorbitol can function as a sweetening agent.

The term “saccharin” refers to the compound chemically designated as1,1-dioxo-1,2-benzothiazol-3-one, having the chemical formula C₇H₅NO₃S,and molar mass 183.18 g/mol. When present in the oral liquid suspensiondescribed herein, the saccharin can function as a sweetening agent.

The saccharin can be saccharin sodium dihydrate powder. The term“saccharin sodium” refers to the sodium salt of saccharin. When presentin the oral liquid suspension described herein, the saccharin sodiumdihydrate powder can function as a sweetening agent.

The term “sucralose” refers to the compound chemically designated as1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside,having the chemical formula C₁₂H₁₉Cl₃O₈, and molar mass 397.64 g/mol.When present in the oral liquid suspension described herein, thesucralose can function as a sweetening agent.

The term “citric acid” refers to the compound chemically designated as2-hydroxypropane-1,2,3-tricarboxylic acid, having the chemical formulaC₆H₈O₇, and molar mass 192.123 g/mol (anhydrous) or 210.038 g/mol(monohydrate). When present in the oral liquid suspension describedherein, the citric acid can function as an acidifying agent,preservative, or combination thereof.

The term “xanthan gum” refers to a polysaccharide having the CAS Number11138-66-2, and chemical formula C₃₅H₄₉O₂₉ (monomer). When present inthe oral liquid suspension described herein, the xanthan gum canfunction as a viscosity-increasing agent, suspending agent, or acombination thereof.

The term “carboxymethyl cellulose,” “carmellose,” or “CMC” refers to acellulose derivative with carboxymethyl groups (—CH₂—COOH) bound to someof the hydroxyl groups of the glucopyranose monomers that make up thecellulose backbone. It is often used as its sodium salt, sodiumcarboxymethyl cellulose. CMC has the CAS Number 9000-11-7. Thecarboxymethyl cellulose can be sodium carboxymethyl cellulose (mediumviscosity, 2% aqueous solution at 25° C. 400-800 cPs). When present inthe oral liquid suspension described herein, the carboxymethyl cellulosecan function as a viscosity-increasing agent, suspending agent, orcombination thereof.

The term “microcrystalline cellulose” or “MCC” is a term for refinedwood pulp. A naturally occurring polymer, it is composed of glucoseunits connected by a 1-4 beta glycosidic bond. These linear cellulosechains are bundled together as microfibril spiraled together in thewalls of plant cell. When present in the oral liquid suspensiondescribed herein, the microcrystalline cellulose can function as asuspending agent.

The term “silicified microcrystalline cellulose” refers to MCC which issilicified. Silicification is the process in which organic matterbecomes saturated with silica. When present in the oral liquidsuspension described herein, the silicified microcrystalline cellulosecan function as a suspending agent.

The term “disodium phosphate” or “DSP” or “sodium hydrogen phosphate” or“sodium phosphate dibasic” refers to the inorganic compound with theformula Na₂HPO₄. and CAS Number 7558-79-4. The disodium phosphate can besodium phosphate dibasic (dried). When present in the oral liquidsuspension described herein, the disodium phosphate can function as a pHmodifying agent.

The term “PROSOLV® SMCC” refers to silicified microcrystallinecellulose, which is a combination of microcrystalline cellulose (MCC)and colloidal silicon dioxide (CSD). The commercial product PROSOLV®SMCC 50M has an average particle size determined by laser diffraction(μm) of 65. The commercial product PROSOLV® SMCC 50M also has a bulkdensity (g/mL) of 0.25-0.37 PROSOLV® SMCC is commercially available fromJRS Pharma (Patterson, N.Y.), https://www.jrspharma.com/pharma_en/.

The term “neurological disorder” refers to any disorder of the nervoussystem. Structural, biochemical or electrical abnormalities in thebrain, spinal cord or other nerves can result in a range of symptoms.Such disorders may be diagnosed by a health care professional.

The term “mental disorder” or “psychiatric disorder” refers to abehavioral or mental pattern that causes significant distress orimpairment of personal functioning. Such features may be persistent,relapsing and remitting, or occur as a single episode. Many disordershave been described, with signs and symptoms that vary widely betweenspecific disorders. Such disorders may be diagnosed by a mental healthprofessional.

The term “epilepsy” refers to a group of neurological disorderscharacterized by epileptic seizures. Epileptic seizures are episodesthat can vary from brief and nearly undetectable periods to long periodsof vigorous shaking. These episodes can result in physical injuries,including occasionally broken bones. In epilepsy, seizures tend to recurand, as a rule, have no immediate underlying cause. Isolated seizuresthat are provoked by a specific cause such as poisoning are not deemedto represent epilepsy. People with epilepsy may be treated differentlyin various areas of the world and experience varying degrees of socialstigma due to their condition.

The term “focal seizures” or “partial seizures” or “partial onsetseizures” refer to localized seizures and are seizures which affectinitially only one hemisphere of the brain. The brain is divided intotwo hemispheres, each consisting of four lobes—the frontal, temporal,parietal and occipital lobes. A focal seizure is generated in andaffects just one part of the brain—a whole hemisphere or part of a lobe.Symptoms will vary according to where the seizure occurs. In the frontallobe symptoms may include a wave-like sensation in the head; in thetemporal lobe, a feeling of déjà vu; in the parietal lobe, numbness ortingling; and in the occipital lobe, visual disturbance orhallucination.

The term “generalized seizures,” as opposed to focal seizures, refer toa type of seizure that impairs consciousness and distorts the electricalactivity of the whole or a larger portion of the brain (which can beseen, for example, on electroencephalography, EEG.

The term “generalized tonic-clonic seizure” or “grand mal seizure”refers to a type of generalized seizure that produces bilateral,convulsive tonic and clonic muscle contractions. Tonic-clonic seizuresare the seizure type most commonly associated with epilepsy and seizuresin general and the most common seizure associated with metabolicimbalances. A tonic-clonic seizure is a convulsion that combines thecharacteristics of tonic (meaning stiffening) and clonic (meaningrhythmical jerking) seizures. The disturbance in functioning is presentin both sides of the brain. The tonic phase comes first (e.g., all themuscles stiffen, air being forced past the vocal cords causes a cry orgroan, and the person loses consciousness and falls to the floor). Afterthe tonic phase comes the clonic phase (e.g., the arms and usually thelegs begin to jerk rapidly and rhythmically, bending and relaxing at theelbows, hips, and knees, and after a few minutes, the jerking slows andstops).

The term “Lennox-Gastaut syndrome” refers to a complex, rare, and severechildhood-onset epilepsy. It is characterized by multiple and concurrentseizure types, cognitive dysfunction, and slow spike waves onelectroencephalogram (EEG). Typically, it presents in children aged 3-5years and can persist into adulthood. It has been associated withseveral gene mutations, perinatal insults, congenital infections, braintumors/malformations, and genetic disorders such as tuberous sclerosisand West syndrome.

The term “generalized seizures of Lennox-Gastaut syndrome” refers togeneralized seizures associated with Lennox-Gastaut syndrome.

The term “antiepileptic drug,” “anticonvulsant,” or “AED” refers to adiverse group of pharmacological agents used in the treatment ofepileptic seizures. Anticonvulsants are also increasingly being used inthe treatment of bipolar disorder and borderline personality disorder,since many seem to act as mood stabilizers, and for the treatment ofneuropathic pain. Anticonvulsants suppress the excessive rapid firing ofneurons during seizures. Anticonvulsants also prevent the spread of theseizure within the brain.

The term “bipolar disorder,” previously known as manic depression,refers to a mental disorder that causes periods of depression andperiods of abnormally elevated mood. The elevated mood is significantand is known as mania or hypomania, depending on its severity, orwhether symptoms of psychosis are present. During mania, an individualbehaves or feels abnormally energetic, happy, or irritable. individualsoften make poorly thought out decisions with little regard to theconsequences. The need for sleep is usually reduced during manic phases.During periods of depression, there may be crying, a negative outlook onlife, and poor eye contact with others.

The term “combination therapy,” “adjunctive therapy,” or “polytherapy”refers to therapy that uses more than one medication or modality (versus“monotherapy,” which is any therapy taken alone). Typically, these termsrefer to using multiple therapies to treat a single disease, and oftenall the therapies are pharmaceutical (although it can also involvenon-medical therapy, such as the combination of medications and talktherapy to treat depression). Monotherapy can be applied to anytherapeutic approach, but it is most commonly used to describe the useof a single medication. Typically, monotherapy is selected because asingle medication is adequate to treat the medical condition. However,monotherapies may also be used because of unwanted side effects ordangerous drug interactions.

The particle size of lamotrigine can be measured by suitable techniquessuch as Laser light scattering (e.g. Malvern Light Scattering), Coultercounter, microscopy, Fraunhofer diffraction and any other techniqueknown in the art. This particle size can be obtained either by the finalstep during the manufacture of the lamotrigine or by the use ofconventional micronizing techniques after the crystallizationprocedure(s).

The term “T_(max)” refers to time of maximum plasma concentration and isthe time to reach maximum (peak) plasma concentration following drugadministration. It is measured in units of time (hours).

The term “t_(1/2)” refers to elimination half-life and is time to reachelimination half-life (to be used in one or non-compartmental model). Itis measured in units of time (hours).

The term “stable” refers to chemical stability, wherein not more than 5wt. % of total related substances are formed on storage at 40° C. and75% relative humidity (R.H.) for a period of 30 days.

The term “shaken” refers to shaken prior to use. For example, a medicalpractitioner or subject (e.g., patient) can shake the oral liquidsuspension prior to administration. The shaking can include vigorouslyshaking by hand, for example, for about 5 to 40 seconds.

The term “release,” “released,” “releasing,” and the like, when used inconnection with a pharmaceutical dosage form, refers to the process orthe portion of the active ingredient that leaves the dosage formfollowing contact with an aqueous environment. Unless otherwiseindicated, the quantity of an active ingredient released from a dosageform is measured by dissolution testing in water as described in thisinvention. The results of the dissolution testing are reported as apercentage (w/w) released as a function of time or as the release time.In some embodiments, complete release of an active ingredient occurswhen at least 90% of the active ingredient has been released from thedosage form.

The term “immediate-release” refers to those which disintegrate rapidlyand/or get dissolved to release the medicaments or active ingredient.

The term “sedimentation volume ratio” or “sedimentation ratio” refers toa ratio of the ultimate volume of sediment (Vu) to the original volumeof sediment (VO) before settling. The sedimentation volume ratio isgenerally achieved within about 5 minutes, 3 minutes, 2 minutes, 60seconds, 45 seconds, or 30 seconds after the powder formulation isreconstituted to the suspension. Various mechanical means, such asshaking, swirling, heating, or any combination thereof can be used topromote a uniform suspension.

The term “subject” refers to a mammal, such as an animal or a human.Hence, the methods disclosed herein can be useful in human therapy andveterinary applications. In one embodiment, the subject is an animal. Inanother embodiment, the subject is a human.

The term “treat” or “treating” refers to attain or attaining abeneficial or desired result, such as a clinical result. In someembodiments, the beneficial or desired result is any one or more of thefollowing: inhibiting or suppressing the onset or development of acondition, reducing the severity of the condition, reducing the numberor severity of symptoms associated with the condition, increasing thequality of life of a patient suffering from the condition, decreasingthe dose of another medication required to treat the condition,enhancing the effect of another medication a patient is taking for thecondition, and prolonging the survival of a patient having thecondition.

The term “D₉₀” refers to the particle size corresponding to 90% of thecumulative undersize distribution by volume.

The term “D₅₀” refers to the particle size corresponding to 50% of thecumulative undersize distribution by volume.

The term “D₁₀” refers to the particle size corresponding to 10% of thecumulative undersize distribution by volume.

It is appreciated that those of skill in the art understand that each ofthe excipients present in the oral liquid suspension provide for one ormore functions. For example, glycerin can function as a preservative,sweetening agent, solvent, viscosity-increasing agent, or anycombination thereof. Formulating an oral liquid suspension to containexcipients that provide multiple functions is beneficial andadvantageous, for example, as the oral liquid suspension can have apleasant taste and/or can have a higher drug load (thereby requiring alower volume to be administered), while achieving the desirablephysicochemical properties and technical attributes.

The viscosity can be measured by using as suitable instrument such asBrookfield viscometer, Haake VT 550 viscometer at room temperature (25°C.).

The oral liquid suspension described herein can be packaged in asuitable pack/container such as amber colored polyethylene terephthalate(PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, lowdensity polyethylene (LDPE) bottle, polypropylene (PP) bottle, the like.The glass or plastic bottle can be provided with a child proof closure.The package can include a syringe or cup (marked in mL, ounces, or both)for ease of dosing. The container such as bottle has a fill volume of,e.g., from about 50 mL to about 500 mL containing the lamotrigine oralliquid suspension. Containers for use in the storage of the oralsuspensions may be used to administer a multiple dose of lamotrigine.

Specific Ranges, Values, Features, and Embodiments

The specific embodiments provided below describing the ranges, values,and features are for illustration purposes only, and do not otherwiselimit the scope of the disclosed subject matter, as defined by theclaims.

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 1±0.2% (w/v).

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 1±0.15% (w/v).

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 1±0.1% (w/v).

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 1±0.005% (w/v).

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 10 mg per milliliter.

In specific embodiments, the oral liquid suspension includeslamotrigine, present in 10±1 mg per milliliter,

In specific embodiments, the oral liquid suspension includes water,present in 84.75±12% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 84.75±10% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 84.75±8.5% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 3.25±0.66% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 3.25±0.5% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 3.25±0.33% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.50% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.37% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.23% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 3.00±0.6% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 3.00±0.45% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 3.00±0.3% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.05% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.025% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.01% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.006% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.0045% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.003% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.42% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.31% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.21% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.016% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.012% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.008% (w/v).

In specific embodiments, the oral liquid suspension includes sucralose,present in 0.75±0.16% (w/v).

In specific embodiments, the oral liquid suspension includes sucralose,present in 0.75±0.12% (w/v).

In specific embodiments, the oral liquid suspension includes sucralose,present in 0.75±0.08% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.03±0.08% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.03±0.006% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.03±0.003% (w/v).

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.20±0.04%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.20±0.06%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.20±0.02%.

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose, present in 0.10±0.02% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose, present in 0.10±0.015% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose, present in 0.10±0.01% (w/v).

In specific embodiments, the oral liquid suspension includes silicifiedmicrocrystalline cellulose, present in 1.26±0.26% (w/v).

In specific embodiments, the oral liquid suspension includes silicifiedmicrocrystalline cellulose, present in 1.26±0.19% (w/v).

In specific embodiments, the oral liquid suspension includes silicifiedmicrocrystalline cellulose, present in 1.26±0.13% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (Microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.5% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.3% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.15% (w/v).

In specific embodiments, the oral liquid suspension includes one or moreflavoring agents.

In specific embodiments, the oral liquid suspension does not include aflavoring agent.

In specific embodiments, the oral liquid suspension includes one or morecolorants.

In specific embodiments, the oral liquid suspension does not include acolorant.

In specific embodiments, the oral liquid suspension includes:

Amount (% w/v) Component  1 ± 0.13,5-diamino-6-(2,3-dichlorophenyl)-as-triazine (lamotrigine) 84.75 ±8.5  water 3.25 ± 0.33 glycerin (99% natural) 2.25 ± 0.23 propyleneglycol 3.00 ± 0.3  polyethylene glycol 400  0.1 ± 0.01 methylparaben 0.03 ± 0.003 sodium benzoate powder 3.0 ± 0.3 70% solution of sorbitol 0.08 ± 0.008 saccharin sodium dihydrate powder 0.75 ± 0.08 sucralose0.20 ± 0.02 xanthan gum sodium carboxymethyl cellulose (medium 0.10 ±0.01 viscosity, 2% aqueous solution at 25° C. 400-800 cPs) 0.03 ± 0.01sodium phosphate dibasic (dried) 1.26 ± 0.15 PROSOLV ® SMCC 50M(microcrystalline cellulose and colloidal silicon dioxide)  0.2 ± 0.02cherry flavor  0.002 ± 0.0002 FD&C red #40  0.0002 ± 0.00002 FD&C yellow#6

In specific embodiments, the oral liquid suspension has a volume of upto 50 mL.

In specific embodiments, the oral liquid suspension has a volume of upto 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL to 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL, 0.5 mL, 2.5 mL, 10 mL, 15 mL, or 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL.

In specific embodiments, the oral liquid suspension has a volume of 0.5mL.

In specific embodiments, the oral liquid suspension has a volume of 2.5mL.

In specific embodiments, the oral liquid suspension has a volume of 10mL.

In specific embodiments, the oral liquid suspension has a volume of 15mL.

In specific embodiments, the oral liquid suspension has a volume of 20mL.

In specific embodiments, the oral liquid suspension has a pH of 6.5-8.0.

In specific embodiments, the oral liquid suspension has a pH of 7-7.3.

In specific embodiments, the oral liquid suspension has a pH of 7.1-7.2.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 100-200 mP.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 100-200

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 100-150 mP.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 110-150 mP.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 110-125 m P

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 117.5±20 mP.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 117.5±10 mP.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 117.5±5 mP.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.3.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.25.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.2.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.05.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.03.

In specific embodiments, the oral liquid suspension is packaged in acontainer.

In specific embodiments, the oral liquid suspension is packaged in anamber colored polyethylene terephthalate (PET) bottle.

In specific embodiments, the oral liquid suspension is packaged in aglass bottle.

In specific embodiments, the oral liquid suspension is packaged in ahigh density polyethylene (HDPE) bottle.

In specific embodiments, the oral liquid suspension is packaged in a lowdensity polyethylene (LDPE) bottle.

In specific embodiments, the oral liquid suspension is packaged in apolypropylene (PP) bottle.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle with a child proof closure.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle and the packaging further includes a syringe orcup, marked in mL, ounces, or both.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle configured for use to administer multiple dosesof lamotrigine.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for a specified periodof time (e.g., ≥20 days, ≥30 days, ≥60 days, ≥90 days, ≥180 days, ≥12months, or ≥24 months) when tested according to <1111>USP-30 NF-25.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes Escherichi a cob (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.1 wt. % Escherichia coli (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.01 wt. % Escherichia coli (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes Burkholderia cepacia complex (BCC).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.1 wt. % Burkholderia cepacia complex (BCC).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.01 wt. % Burkholderia cepacia complex (BCC).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 24 monthsunder ambient conditions.

Int specific embodiments, the oral liquid suspension, while packaged ina container, is free from microbial contamination for at least 12 monthsunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 6 monthsunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 180 daysunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 90 daysunder ambient conditions.

In specific embodiments, the oral liquid suspension is an immediaterelease dosage form.

In specific embodiments, the oral liquid suspension exhibitsredispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 80% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 85% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 90% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 95% redispersibility.

In specific embodiments, the oral liquid suspension is an immediaterelease dosage form that exhibits in-vitro dissolution rate more than85% of drug release within 15 minutes, when said dosage form is placedin a dissolution vessel filled with 900 ml of 0.1 N HCL, pH 1.2maintained at 37±0.5° C. and stirred at a paddle speed of 50 rpm using aUSP Type II (paddle) apparatus.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 200 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 175 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 150 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 140 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 100 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 90 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 80 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₃₀ of not more than 63 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 30 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 29 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 27 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 26 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas the following particle size distribution:

-   -   D₉₀ of not more than 200 microns;    -   D₅₀ of not more than 100 microns; and    -   D₁₀ of not more than 30 microns.

In specific embodiments, the lamotrigine in the oral liquid suspensionhas the following particle size distribution:

-   -   D₉₀ of not more than 140 microns;    -   D₅₀ of not more than 63 microns; and    -   D₁₀ of not more than 26 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₉₀ of notmore than 90 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₉₀ of notmore than 80 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has a particle size distribution D₉₀ of notmore than 70 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has a particle size distribution D₅₀ of notmore than 50 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₅₀ of notmore than 40 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₅₀ of notmore than 30 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₁₀ of notmore than 30 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has a particle size distribution D₁₀ of notmore than 20 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₁₀ of notmore than 10 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has the following particle size distribution:

-   -   D₉₀ of not more than 70 microns;    -   D₅₀ of not more than 30 microns; and    -   D₁₀ of not more than 10 microns.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension is amorphous.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension is crystalline.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral liquid suspension has a water content of not more than 1.0 wt.%.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has a water content of not more than 0.75 wt.%.

In specific embodiments, the lamotrigine employed in the manufacture ofthe oral iquid suspension has a water content of not more than 0.5 wt.%.

In specific embodiments, the oral liquid suspension is administered to asubject that is a human.

In specific embodiments, the oral liquid suspension is administered to asubject human adult of at least 16 years in age (i.e., aged 16 years orolder).

In specific embodiments, the oral liquid suspension is administered to asubject that is a human adult of at least 18 years in age (i.e., aged 18years or older).

In specific embodiments, the oral liquid suspension is administered to asubject that is a human of less than 16 years in age.

In specific embodiments, the oral liquid suspension is administered to asubject that is a human aged 2 years or older (i.e., aged 2 years orolder).

In specific embodiments, the oral liquid suspension is administered totreat at least one of a neurological disorder and a mental disorder in asubject.

In specific embodiments, the oral liquid suspension is administered totreat a neurological disorder in a subject.

In specific embodiments, the oral liquid suspension is administered totreat a mental disorder in a subject.

In specific embodiments, the oral liquid suspension is administered totreat at least one of a neurological disorder and a mental disorder in asubject, wherein the disorder comprises at least one of (a)-(c):

(a) epilepsy—adjunctive therapy in a subject aged 2 years and older:

partial-onset seizures

primary generalized tonic-clonic seizures

generalized seizures of Lennox-Gastaut syndrome

(b) epilepsy—monotherapy in a subject aged 16 years and older:Conversion to monotherapy in a subject with partial-onset seizures whoare receiving treatment with carbamazepine, phenytoin, phenobarbital,primidone, or valproate as the single AED(c) bipolar disorder: maintenance treatment of bipolar I disorder todelay the time to occurrence of mood episodes in a subject treated foracute mood episodes with standard therapy.

In specific embodiments, the disorder is epilepsy.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatepilepsy.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatpartial-onset seizures.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatprimary generalized tonic-clonic seizures.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatgeneralized seizures of Lennox-Gastaut syndrome.

In specific embodiments, the oral liquid suspension is administered as amonotherapy to a subject aged 16 years or older, to treat epilepsy.

In specific embodiments, the oral liquid suspension is administered as amonotherapy to a subject aged 16 years or older with partial-onsetseizures, to treat epilepsy, wherein the subject is undergoingconversion to monotherapy and is receiving treatment with carbamazepine,phenytoin, phenobarbital, primidone, or valproate as the single AED.

In specific embodiments, the oral liquid suspension is administered to asubject to treat bipolar disorder.

In specific embodiments, the oral liquid suspension is administered to asubject for maintenance treatment of bipolar I disorder, to delay thetime to occurrence of mood episodes in the subject treated for acutemood episodes with standard therapy.

In specific embodiments, the oral liquid suspension is administered,such that

-   -   2±0.2 mg lamotrigine in 0.2 mL of the oral liquid suspension, or    -   5±0.5 mg lamotrigine in 0.5 mL of the oral liquid suspension, or    -   25±2.5 mg lamotrigine in 2.5 mL of the oral liquid suspension,        or    -   100±10.0 mg lamotrigine in 10 mL of the oral liquid suspension,        or    -   150±15.0 mg lamotrigine in 15 mL of the oral liquid suspension,        or    -   200±20.0 mg lamotrigine in 20 mL of the oral liquid suspension        is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 2±0.2 mg lamotrigine in 0.2 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 5±0.5 mg lamotrigine in 0.5 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 25±2.5 mg lamotrigine in 2.5 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 100±10.0 mg lamotrigine in 10 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 150±15.0 mg lamotrigine in 15 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 200±20.0 mg lamotrigine in 20 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: AUC, 0→24(micrograms per hour per ml) of 88.1—198.8.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: AUC, 0→24(micrograms per hour per ml) of 142.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: C_(max)(micrograms per ml) steady state of 5.01-12.5.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: C_(max)(micrograms per ml) steady state of 7.93.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: T_(max)(h)of 0.00-8.0.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: T_(max)(h)of 2.79.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 14.0-103.0 (single dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 32.8 (single dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 11.6-61.6 (multiple dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 25.4 (multiple dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including:

-   -   AUC, 0→24 (micrograms per hour per ml) of 88.1-198.8;    -   C_(max) (micrograms per ml) steady state of 5.01-12.5;    -   T_(max)(h) of 0.00-8.0;    -   t_(1/2)(h) of 14.0-103.0 (single dose); and    -   t_(1/2)(h) of 11.6-61.6 (multiple dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a single-dose administration pharmacokinetic (PK)profile including:

-   -   AUC, 0→24 (micrograms per hour per ml) of 142;    -   C_(max) (micrograms per ml) steady state of 7.93;    -   T_(max)(h) of 2.79;    -   t_(1/2)(h) of 32.8 (single dose); and    -   t_(1/2)(h) of 25.4 (multiple dose).

In specific embodiments, relative to oral tablets or chewabledispersible tablets containing an equivalent amount of lamotrigine,administration of the oral liquid suspension results in a lowerincidence, severity, and/or duration of adverse reactions including atleast one of dizziness, headache, diplopia, ataxia, nausea, blurredvision, somnolence, rhinitis, pharyngitis, rash, vomiting, infection,fever, accidental injury, diarrhea, abdominal pain, tremor, backpain,fatigue, and xerostomia.

1. An oral liquid suspension comprising:3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine (lamotrigine); water;glycerin; propylene glycol; polyethylene glycol; methylparaben; sodiumbenzoate; sorbitol; saccharin; sucralose; xanthan gum; carboxymethylcellulose; sodium phosphate; and PROSOLV® SMCC 50M (microcrystallinecellulose and colloidal silicon dioxide).
 2. The oral liquid suspensionof claim 1, wherein the lamotrigine is present in 10 mg/mL.
 3. The oralliquid suspension of claim 1, wherein the lamotrigine present in theoral liquid suspension has the following particle size distribution(PSD): D₉₀ of not more than 200 microns, D₅₀ of not more than 100microns, and D₁₀ of not more than 30 microns.
 4. The oral liquidsuspension of claim 1, wherein the lamotrigine present in the oralliquid suspension has the following particle size distribution (PSD):D₉₀ of not more than 140 microns, D₅₀ of not more than 63 microns, andD₁₀ of not more than 26 microns.
 5. The oral liquid suspension of claim1, having a viscosity at 25° C. of 100-200 mPs.
 6. The oral liquidsuspension of claim 1, having a viscosity at 25° C. of 117.5±10 mPs. 7.The oral liquid suspension of claim 1, having a pH of 6.5-8.0.
 8. Theoral liquid suspension of claim 1, having a pH of 7.1-7.2.
 9. The oralliquid suspension of claim 1, having a specific gravity of not more than1.2.
 10. The oral liquid suspension of claim 1, having a specificgravity of not more than 1.03.
 11. The oral liquid suspension of claim1, further comprising a flavoring agent.
 12. The oral liquid suspensionof claim 1, further comprising cherry flavor as a flavoring agent. 13.The oral liquid suspension of claim 1, further comprising a coloringagent.
 14. The oral liquid suspension of claim 1, further comprisingFD&C red #40 and FD&C yellow #6 as a coloring agent.
 15. The oral liquidsuspension of claim 1, comprising: Amount (% w/v) Component  1 ± 0.13,5-diamino-6-(2,3-dichlorophenyl)-as- triazine (lamotrigine) 84.75 ±8.5  water 3.25 ± 0.33 glycerin (99% natural) 2.25 ± 0.23 propyleneglycol 3.00 ± 0.3  polyethylene glycol 400  0.1 ± 0.01 methylparaben 0.03 ± 0.003 sodium benzoate powder 3.0 ± 0.3 70% solution of sorbitol 0.08 ± 0.008 saccharin sodium dihydrate powder 0.75 ± 0.08 sucralose0.20 ± 0.02 xanthan gum 0.10 ± 0.01 sodium carboxymethyl cellulose(medium viscosity, 2% aqueous solution at 25° C. 400- 800 cPs) 0.03 ±0.01 sodium phosphate dibasic (dried) 1.26 ± 0.15 PROSOLV ® SMCC 50M(microcrystalline cellulose and colloidal silicon dioxide)  0.2 ± 0.02cherry flavor  0.002 ± 0.0002 FD&C red #40  0.0002 ± 0.00002 FD&C yellow#6


16. The oral liquid suspension of claim 1, having a volume of 0.2 mL,0.5 mL, 2.5 mL, 10 mL, 15 mL, or 20 mL.
 17. The oral liquid suspensionof claim 1, while packaged in a container, is essentially free frommicrobial growth for at least 24 months under ambient conditions. 18.The oral liquid suspension of claim 1, while packaged in a container, isessentially free from Escherichia coli (E. coli) for at least 24 monthsunder ambient conditions.
 19. The oral liquid suspension of claim 1,while packaged in a container, is essentially free from Burkholderiacepacia complex (BCC) for at least 24 months under ambient conditi ons,20. The oral liquid suspension of claim 1, which is an immediate releasedosage form.
 21. The oral liquid suspension of claim 1, which is animmediate release dosage form that exhibits in-vitro dissolution ratemore than 85% of drug release within 15 minutes, when said dosage formis placed in a dissolution vessel filled with 900 ml of 0.1 N HCL, pH1.2 maintained at 37±0.5° C. and stirred at a paddle speed of 50 rpmusing a USP Type II (paddle) apparatus.
 22. A method for treating atleast one of a neurological disorder and a mental disorder in a subject,the method comprising administering to a subject suffering from thedisorder 0.1-25.0 mL of the oral liquid suspension of claim
 1. 23. Themethod of claim 22, wherein the disorder comprises at least one of(a)-(c): (a) epilepsy adjunctive therapy in a subject aged 2 years orolder: partial-onset seizures primary generalized tonic-clonic seizuresgeneralized seizures of Lennox-Gastaut syndrome (b) epilepsy—monotherapyin a subject aged 16 years and older: Conversion to monotherapy in asubject with partial-onset seizures who are receiving treatment withcarbamazepine, phenytoin, phenobarbital, primi done, or valproate as thesingle AED (c) bipolar disorder: maintenance treatment of bipolar Idisorder to delay the time to occurrence of mood episodes in a subjecttreated for acute mood episodes with standard therapy.
 24. The method ofclaim 22, wherein the oral liquid suspension is administered, such that2±0.2 mg lamotrigine in 0.2 mL of the oral liquid suspension, or 5±0.5mg lamotrigine in 0.5 mL of the oral liquid suspension, or 25±2.5 mglamotrigine in 2.5 mL of the oral liquid suspension, or 100±10.0 mglamotrigine in 10 mL of the oral liquid suspension, or 150±15.0 mglamotrigine in 15 mL of the oral liquid suspension, or 200±20.0 mglamotrigine in 20 mL of the oral liquid suspension is delivered to thesubject.
 25. The method of claim 22, wherein upon administration underfasted conditions of a healthy adult subject with epilepsy taking noother medications, the oral liquid suspension exhibits a single-doseadministration pharmacokinetic (PK) profile including: AUC, 0→24(micrograms per hour per ml) of 142; C_(max) (micrograms per ml) steadystate of 7.93; T_(max)(h) of 2.79; t_(1/2)(h) of 32.8 (single dose); andt_(1/2)(h) of 25.4 (multiple dose).
 26. The method of claim 22, whereinrelative to oral tablets or chewable dispersible tablets containing anequivalent amount of lamotrigine, administration of the oral liquidsuspension results in a lower incidence, severity, and/or duration ofadverse reactions including at least one of dizziness, headache,diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis,pharyngitis, rash, vomiting, infection, fever, accidental injury,diarrhea, abdominal pain, tremor, backpain, fatigue, and xerostomia.